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Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways
Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective ef...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838126/ https://www.ncbi.nlm.nih.gov/pubmed/33519417 http://dx.doi.org/10.3389/fnagi.2020.587403 |
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author | Li, Wenxian Wei, Di Zhu, Zheng Xie, Xiaomei Zhan, Shuqin Zhang, Ru Zhang, Guilian Huang, Li’an |
author_facet | Li, Wenxian Wei, Di Zhu, Zheng Xie, Xiaomei Zhan, Shuqin Zhang, Ru Zhang, Guilian Huang, Li’an |
author_sort | Li, Wenxian |
collection | PubMed |
description | Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH. |
format | Online Article Text |
id | pubmed-7838126 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78381262021-01-28 Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways Li, Wenxian Wei, Di Zhu, Zheng Xie, Xiaomei Zhan, Shuqin Zhang, Ru Zhang, Guilian Huang, Li’an Front Aging Neurosci Neuroscience Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH. Frontiers Media S.A. 2021-01-13 /pmc/articles/PMC7838126/ /pubmed/33519417 http://dx.doi.org/10.3389/fnagi.2020.587403 Text en Copyright © 2021 Li, Wei, Zhu, Xie, Zhan, Zhang, Zhang and Huang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Li, Wenxian Wei, Di Zhu, Zheng Xie, Xiaomei Zhan, Shuqin Zhang, Ru Zhang, Guilian Huang, Li’an Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways |
title | Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways |
title_full | Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways |
title_fullStr | Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways |
title_full_unstemmed | Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways |
title_short | Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways |
title_sort | dl-3-n-butylphthalide alleviates hippocampal neuron damage in chronic cerebral hypoperfusion via regulation of the cntf/cntfrα/jak2/stat3 signaling pathways |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838126/ https://www.ncbi.nlm.nih.gov/pubmed/33519417 http://dx.doi.org/10.3389/fnagi.2020.587403 |
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